Evaluating the Aqueous Stability of Alkyl-/Aryl-Hydrosilanes by NMR Spectroscopy and GC-MS and development of hydrosilafluorenes as recyclable coupling reagents for direct amidation

Candidate: Fawwaz Azam
Supervisor: Dr. Marc Adler

Abstract:

Hydrosilanes are commonly used as reducing agents or as precursors for silanols. However, the incorporation of hydrosilanes as a carbon bioisostere in bioapplied molecules is under-reported. In this study, the hydrolytic stability of ten representative hydrosilanes – featuring a range of substitutions on the silicon: monoaryl, monoalkyl, diaryl, dialkyl, alkyl aryl, triaryl, trialkyl, dialkyl aryl, and alkyl diaryl – was investigated using five complimentary methods including 1H-NMR time-lapse and GC-MS experiments under neutral pH. The 1H-NMR timelapse experiments suggest that monoaryl and monoalkyl silanes are readily susceptible to hydrolysis under the mixed solvent conditions used, as evidenced by a 31% and 22% reduction in starting material concentration, respectively, over 24 hours. On the other hand, diaryl-, dialkyl-, alkylaryl-, triaryl-, trialkyl-, dialkylaryl-, and alkyldiaryl silanes are resistant to hydrolysis in these solvent systems for up to at least 24 hours. The GC-MS experiments provide quantitative data to support the reactivity of these hydrosilanes at pH 7. Lastly, the reactivity of selected hydrosilanes were evaluated pH 7.4 (PBS buffer). Monoalkyl silanes degraded in the presence of the added salt content while the remaining hydrosilanes were resistant to hydrolysis. Overall, the study demonstrates that hydrosilanes exhibit hydrolytic stability at neutral pH, with the exception of monoaryl- and monoalkyl-substituted silanes, which are susceptible to degradation. The results provide insight into the likeliness of the Si-H bond surviving in aqueous environments, which could open the door for a wider variety of silicon containing molecules in drug discovery.

Amides are responsible for the structural integrity of proteins, are an important component of synthetic polymers, and are present in over half of the top 200 small molecule drugs sold in 2023. For these reasons, amidation reactions are one of the most frequently performed reactions in chemistry. Current state-of-the-art routes to access amides are efficient, however, improvements can be made to the safety of reagents and atom economy to make the reaction more sustainable. In this regard, organosilanes are emerging as alternative amide coupling reagents because of their ease-of-handling and low toxicity of reagents/by-product. With this in mind, we envisioned constraining an organosilane into a small-membered ring silacycle to make use of “strain-release Lewis acidity”. Silafluorenes 9-methyl-9H-9-silafluorene and 9-phenyl-9H-9-silafluorene were selected because the hydrosilanes are easier to handle (e.g., stable in open air) than the chlorosilane derivatives. In this work, we have discovered both 9-methyl-9H-9-silafluorene and 9-phenyl-9H-9-silafluorene as effective reagents for direct amidation of carboxylic acids with amines. The protocol is performed under open-air conditions without rigorous exclusion of moisture, producing amides in high yields with only H2 and disiloxane as by-products. The disiloxane by-product can be reduced in a separate step to recycle the silafluorenes.